Tris(2-chloroethyl)phosphate increases ambulatory activity in mice: pharmacological analyses of its neurochemical mechanism.
The present study was conducted to clarify the acute effect of tris(2-chloroethyl)phosphate (TRCP), an organophosphate flame-retardant, on spontaneous ambulatory activity (AA) in male ICR mice and to examine the neurochemical mechanism of this effect. Single dose administration of 200 mg/kg i.p. of TRCP increased AA in ICR mice. Neither the nicotinic cholinergic antagonist mecamylamine (MA) nor the muscarinic cholinergic antagonist scopolamine (SCP) affected the AA response to TRCP. On the other hand, the benzodiazepine agonist diazepam (DZ), the GABAA agonist muscimol (MUS) and the GABAB agonist baclofen (BAC) all attenuated the effect of TRCP. DZ and MUS blocked the increase of AA within the first 10 min after administration of TRCP. These drugs did not attenuate the AA-increasing effect of SCP, suggesting that the mechanism of TRCP action is distinct from that of SCP. MUS and BAC did, but DZ did not, inhibit the AA increasing effect of the dopaminergic agonist apomorphine (APO), suggesting that dopamine is involved in the control of AA, and that GABA can affect AA through interaction with dopaminergic neurons. These results suggest that TRCP acts as a GABA antagonist and not as a cholinergic agonist, and that TRCP increases AA in ICR mice through a GABAergic mechanism.
Umezu
T
T
Regional Environment Division, National Institute for Environmental Studies, Ibaraki, Japan.
Yonemoto
J
J
Soma
Y
Y
Suzuki
T
T
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects*; D003975:Diazepam / Q000494:pharmacology; D004338:Drug Combinations; D005411:Flame Retardants / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010755:Organophosphates / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012640:Seizures / Q000139:chemically induced
D014151:Anti-Anxiety Agents; D004338:Drug Combinations; D005411:Flame Retardants; D018755:GABA Agonists; D018756:GABA Antagonists; D018727:Muscarinic Antagonists; D018733:Nicotinic Antagonists; D010755:Organophosphates; C031324:tris(chloroethyl)phosphate; D003975:Diazepam